Synthesis of n-[n-(3,3-dimethylbutyl)-l-alpha-aspartyl]-l-phenylalanine 1-methyl ester using 3,3-dimethylbutyraldehyde precursors

ABSTRACT

N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is produced by hydrogenation of L-α-aspartyl-L-phenylalanine 1-methyl ester and 3,3-dimethylbutyraldehyde produced in situ by the hydrolysis or cleavage of a 3,3-dimethylbutyraldehyde precursor. The production method is efficient and low cost, as compared with conventional N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester synthesis.

This application is a divisional application of U.S. patent applicationSer. No. 10/834,933, filed Apr. 30, 2004, which claims the benefit ofU.S. Provisional Application No. 60/468,076, filed May 6, 2003, thedisclosures of each of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the synthesis ofN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester(neotame) using 3,3-dimethylbutyraldehyde precursors. This method ofproducing neotame is more simple and more economical than theconventional preparation of neotame.

2. Related Background Art

N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester(neotame) is a high potency dipeptide sweetener (about 8000× sweeterthan sucrose) that has the formula

The chemical synthesis of neotame is disclosed in U.S. Pat. No.5,480,668, U.S. Pat. No. 5,510,508, U.S. Pat. No. 5,728,862 and WO00/15656, the disclosure of each of which is incorporated by referenceherein.

U.S. Pat. Nos. 5,510,508 and 5,728,862 describe the synthesis of neotameby hydrogenation of a mixture of aspartame and 3,3-dimethylbutyraldehydewith a catalyst such as Pd on carbon. This synthesis is represented bythe following equation.

The 3,3-dimethylbutyraldehyde used in this synthesis is typicallyproduced from the bisulfite adduct of 3,3-dimethylbutyraldehyde bytreatment with base, followed by distillation as described in U.S. Pat.No. 5,905,175, the disclosure of which is incorporated by referenceherein. The above-noted neotame process requires the reaction of pureisolated aspartame with pure isolated aldehyde to produce neotame.However, it would be economically advantageous to use3,3-dimethylbutyraldehyde precursors directly in neotame synthesiswithout having to first isolate 3,3-dimethylbutyraldehyde in order toeconomically and efficiently produce pureN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester.

SUMMARY OF THE INVENTION

The present invention relates to the efficient, low cost and high puritysynthesis of N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine1-methyl ester (neotame). According to one embodiment of the presentinvention, neotame is synthesized by reacting aspartame and3,3-dimethylbutyraldehyde dimethyl acetal in a solvent or a mixture ofsolvents under hydrogenation conditions with a catalyst.

In a second embodiment of the present invention, neotame is synthesizedby first hydrolyzing a bisulfite adduct of 3,3-dimethylbutyraldehydewith a base in a solvent or a mixture of solvents and then addingaspartame under hydrogenation conditions with a catalyst to produceneotame.

In a third embodiment of the present invention, neotame is synthesizedby regenerating 3,3-dimethylbutyraldehyde from a hydrazone,semicarbazone or oxime of 3,3-dimethylbutyraldehyde by acidic hydrolysisor by oxidative cleavage in a solvent or a mixture of solvents and thenadding aspartame under hydrogenation conditions with a catalyst toproduce neotame.

In a fourth embodiment of the present invention, neotame is synthesizedby hydrolyzing a trimer of 3,3-dimethylbutyraldehyde with an acid in asolvent or a mixture of solvents and then adding aspartame underhydrogenation conditions with a catalyst to produce neotame.

DETAILED DESCRIPTION

The present invention relates to the synthesis ofN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester(neotame) by catalyzed hydrogenation of L-α-aspartyl-L-phenylalanine1-methyl ester (aspartame) and 3,3-dimethylbutyraldehyde produced insitu by the hydrolysis or cleavage of a 3,3-dimethylbutyraldehydeprecursor. More specifically, a precursor of 3,3-dimethylbutyraldehydeis hydrolyzed or cleaved to produce the aldehyde which is then used insitu to produce neotame, thereby eliminating the need to isolate3,3-dimethylbutyraldehyde prior to its combination with aspartame.Precursors of 3,3-dimethylbutyraldehyde suitable for use in the presentinvention include 3,3-dimethylbutyraldehyde dimethyl acetal, thebisulfite adduct of 3,3-dimethylbutyraldehyde, the hydrazone,semicarbazone or oxime of 3,3-dimethylbutyraldehyde and the trimer of3,3-dimethylbutyraldehyde.

According to the first embodiment of the present invention,N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester issynthesized by reacting aspartame and 3,3-dimethylbutyraldehyde dimethylacetal (RR′=(OCH₃)₂) in a solvent or a mixture of solvents underhydrogenation conditions, i.e., in the presence of hydrogen, with acatalyst according to the following scheme:

3,3-Dimethylbutyraldehyde dimethyl acetal suitable for use in thepresent invention may be obtained via the procedures outlined in“Protection for the Carbonyl Group”, T. W. Greene, et al., ProtectiveGroups in Organic Synthesis, 2d ed., John Wiley & Sons, New York,chapter 4, 1991. The 3,3-dimethylbutyraldehyde dimethyl acetal can beused in situ from its precursors in any known synthetic route (seeabove).

There is no need to hydrolyze the 3,3-dimethylbutyraldehyde dimethylacetal prior to the addition to aspartame; however, if desired, theprocess of the first embodiment of this invention can be carried out inseparate hydrolysis and hydrogenation steps. According to thisinvention, 3,3-dimethylbutyraldehyde is not isolated prior to theaddition of aspartame; instead it is reacted in situ with aspartame toproduce neotame. Generally the concentration of the3,3-dimethylbutyraldehyde dimethyl acetal, and, in effect, theconcentration of the 3,3-dimethylbutyraldehyde produced in situ, in thehydrogenation mixture is preferably in a range of about 0.90 to about1.1, more preferably about 0.98 to about 1.0 on an equivalent molarratio basis with aspartame.

According to the second embodiment of the present invention, neotame issynthesized by hydrolyzing a bisulfite adduct of3,3-dimethylbutyraldehyde with a base in a solvent or a mixture ofsolvents to produce 3,3-dimethylbutyraldehyde in situ and then reactingthe aldehyde with aspartame under hydrogenation conditions with acatalyst according to the following scheme:

A bisulfite adduct of 3,3-dimethylbutyraldehyde (RR′=OH(SO₃Na)) suitablefor use in the present invention may be obtained according to theprocedure set forth in U.S. Pat. No. 5,905,175. The bisulfite adduct of3,3-dimethylbutyraldehyde used in the present inventive process can be awet cake, a dry cake or a solution in water. The bisulfite adduct of3,3-dimethylbutyraldehyde can be used in situ from its precursors in anyknown synthetic route (see above).

Importantly, the bisulfite adduct of 3,3-dimethylbutyraldehyde must behydrolyzed prior to the addition of aspartame. Again, however, accordingto this invention, 3,3-dimethylbutyraldehyde is not isolated prior tothe addition of aspartame; instead the hydrolysis product of thebisulfite adduct of 3,3-dimethylbutyraldehyde is reacted in situ withaspartame to produce neotame. Generally the concentration of thebisulfite adduct used, and, in effect, the concentration of the3,3-dimethylbutyraldehyde produced in situ, is preferably in a range ofabout 0.90 to about 1.1, more preferably about 0.98 to about 1.0 on anequivalent molar ratio basis with aspartame.

Bases suitable for use in the present invention include, withoutlimitation, sodium bicarbonate, potassium bicarbonate, sodium carbonate,potassium carbonate, zinc oxide, zinc carbonate, magnesium oxide,calcium oxide, aluminum oxide, magnesium carbonate, calcium carbonate,monobasic potassium phosphate, dibasic potassium phosphate, tribasicpotassium phosphate, monobasic sodium phosphate, dibasic sodiumphosphate, tribasic sodium phosphate, ammonium phosphate, calciumphosphate, magnesium phosphate, ammonia, a tertiary amine, a secondaryamine, a pyridine derivative, or a mixture thereof. Generally the amountof the base used is preferably in a range of about 1% to about 10%, morepreferably about 1% to about 2% by weight based on the amount of thebisulfite adduct.

According to the third embodiment of the present invention, neotame issynthesized by regenerating 3,3-dimethylbutyraldehyde from a hydrazone,semicarbazone or oxime of 3,3-dimethylbutyraldehyde by acidic hydrolysisor oxidative cleavage in a solvent or a mixture of solvents to produce3,3-dimethylbutyraldehyde in situ and then reacting the aldehyde withaspartame under hydrogenation conditions with a catalyst according tothe following scheme:

A hydrazone (RR′=NOH), semicarbazone (RR′=NNHCONH₂) or oxime (RR′=NNHPh)of 3,3-dimethylbutyraldehyde suitable for use in the present inventionmay be obtained via the procedures outlined in “Protection for theCarbonyl Group”, T. W. Greene, et al., Protective Groups in OrganicSynthesis, 2d ed., John Wiley & Sons, New York, chapter 4, 1991. Thehydrazone, semicarbazone or oxime of 3,3-dimethylbutyraldehyde used inthe present inventive process can be a wet cake or a dry cake. Thehydrazone, semicarbazone or oxime of 3,3-dimethylbutyraldehyde can beused in situ from its precursors in any known synthetic route (seeabove).

Importantly, the hydrazone, semicarbazone or oxime of3,3-dimethylbutyraldehyde must be hydrolyzed or cleaved prior to theaddition of aspartame. Again, however, according to this invention,3,3-dimethylbutyraldehyde is not isolated prior to the addition ofaspartame; instead the hydrolysis or cleaved product of the hydrazone,semicarbazone or oxime of 3,3-dimethylbutyraldehyde is reacted in situwith aspartame to produce neotame. Generally the concentration of thehydrazone, semicarbazone or oxime of 3,3-dimethylbutyraldehyde used,and, in effect, the concentration of the 3,3-dimethylbutyraldehydeproduced in situ, is preferably in a range of about 0.90 to about 1.1,more preferably about 0.98 to about 1.0 on an equivalent molar ratiobasis with aspartame.

Acids suitable for use in the acid hydrolysis of this embodiment of thepresent invention include, without limitation, acetic acid, citric acid,nitrous acid and combinations thereof. Generally the concentration ofthe acid in the solvent is preferably in a range of about 1% to about5%, more preferably about 1% to about 2% by weight of the amount ofhydrazone, semicarbazone or oxime of 3,3-dimethylbutyraldehyde.

Oxidative agents suitable for use in the oxidative cleavage of thisembodiment of the present invention include, without limitation,m-chloroperbenzoic acid, ozone, any hypervalent iodine agent such assodium periodate, diacetoxyiodobenzene and iodosobenzene, andcombinations thereof. Generally the concentration of the oxidative agentin the solvent is preferably in a range of about 0.5 to about 3, morepreferably about 0.9 to about 1.1 on an equivalent molar ratio basiswith the hydrazone, semicarbazone or oxime of 3,3-dimethylbutyraldehyde.

According to the fourth embodiment of the present invention, neotame issynthesized by hydrolyzing a trimer of 3,3-dimethylbutyraldehyde with anacid in a solvent or a mixture of solvents to produce3,3-dimethylbutyraldehyde in situ and then reacting the aldehyde withaspartame under hydrogenation conditions with a catalyst according tothe following scheme:

The trimer of 3,3-dimethylaldehyde suitable for use in the presentinvention may be obtained via the procedure set forth in Example 3 belowor via any known synthetic route. The trimer can be used in situ fromits precursors in any known synthetic route (see above).

Importantly, the trimer of 3,3-dimethylbutyraldehyde must be hydrolyzedprior to the addition of aspartame. Again, however, according to thisinvention, 3,3-dimethylbutyraldehyde is not isolated prior to theaddition of aspartame; instead the hydrolysis product of the trimer of3,3-dimethylbutyraldehyde is reacted in situ with aspartame to produceneotame. Generally the concentration of the trimer of3,3-dimethylbutyraldehyde used is in a range of about 0.3 to about 1.1,more preferably about 0.33 to about 0.35 on an equivalent molar ratiobasis with aspartame.

Acids suitable for use in this embodiment of the present inventioninclude, without limitation, hydrochloric acid, acetic acid, sulfuricacid, and combinations thereof. Generally the concentration of the acidin the solvent is in a range of about 1% to about 20%, more preferablyabout 1% to about 10% by weight of the amount of trimer.

It is important to note that the hydrolysis or cleavage of the aldehydeprecursor in each of the second, third and fourth embodiments of thisinvention can be accomplished via any known means. In addition, for eachof these embodiments, an optional neutralization step may be required ifan acid or a base is used in the hydrolysis or cleavage step. Inparticular, the pH of the solvent containing the aldehyde is preferablyin a range of about 3 to about 7 prior to the addition of the aspartamefor hydrogenation. If the pH of the solvent containing the aldehyde isnot in such a range, then a neutralization step is required;neutralization can be accomplished by any known suitable means.

The remaining description of the parameters for the synthesis of neotameis applicable to each of the above-noted embodiments of the presentinvention.

Aspartame suitable for use in the present invention is commerciallyavailable or can be synthesized according to known methods. Further,pending U.S. patent application Ser. No. 09/859,438, filed May 18, 2001,is directed to the use of aspartame precursors in the synthesis ofneotame; such aspartame precursors are also suitable for use in thepresent invention.

Solvents suitable for use in the present invention include, withoutlimitation, ethanol, ethyl acetate, acetonitrile, dioxane, methanol,isopropanol, isobutyl methyl ketone, tetrahydrofuran, cyclohexane,toluene, dimethylformamide (DMF), water and mixtures thereof. Thesolvent can be added to a dry cake of a reactant, i.e., a3,3-dimethylbutyraldehyde precursor or aspartame. Alternatively, thesolvent may be used in situ in the formation of a3,3-dimethylbutyraldehyde precursor, or it may be added to a reactionmixture.

The catalyst suitable for use in the present invention may be selectedfrom catalysts based on palladium or platinum including, withoutlimitation, platinum on activated carbon, palladium on activated carbon,platinum black or palladium black. Other catalysts include, withoutlimitation, nickel on silica, nickel on alumina, Raney nickel, rutheniumblack, ruthenium on carbon, palladium hydroxide on carbon, palladiumoxide, platinum oxide, rhodium black, rhodium on carbon, rhodium onalumina and mixed catalysts as described in pending U.S. applicationSer. No. 10/010,381 filed Mar. 28, 2002. The catalysts based onpalladium or platinum are preferred.

The catalyst is present in an amount effective to produce neotame in anacceptable rate and yield. Generally, the weight ratio of catalyst (on adry basis) to aspartame is about 0.01:1 to about 0.25:1, preferablyabout 0.10:1. It is important to note that about a 10% catalyst loadingis required to minimize the undesirable yield of dialkylated aspartame.

The 3,3-dimethylbutyraldehyde and aspartame are typically combined in asubstantially equivalent molar ratio, i.e., about 1:0.95 to 1:1. Excessmolar amounts of aspartame are not preferred due to waste and cost.Higher molar amounts of the aldehyde precursor, and, in effect, thealdehyde are likely to lead to the generation of impurities.

The 3,3-dimethylbutyraldehyde produced in situ and aspartame are reactedfor a time and at a temperature sufficient to produce neotame.Generally, the time sufficient to produce the aldehyde in situ rangesfrom about 0.5 to about 48 hours. Generally, the time sufficient toproduce neotame ranges preferably from about 1 to about 24 hours, morepreferably from about 6 to about 24 hours. Generally, the temperaturesufficient to produce neotame according to the present invention rangespreferably from about 20° C. to about 60° C., more preferably from about22° C. to about 40° C.

The reactions of the present invention are carried out in the presenceof hydrogen. Generally, the pressure of the hydrogen ranges from about 5psi to about 100 psi, preferably from about 30 psi to about 50 psi.

The present invention may also include additional steps. Such additionalsteps include, without limitation, catalyst removal, solventconcentration adjustment, holding, seeding, cooling (crystallization),and neotame isolation.

The catalyst may be separated by a variety of solid-liquid separationtechniques that include, without limitation, the use of sparkler,crossflow, nutsche, basket, belt, disc, drum, cartridge, candle, leafand bag filters. Furthermore, catalyst separation performance may beenhanced through the use of gravity, pressure, vacuum and/or centrifugalforce. Additionally, the catalyst separation rate and removal efficiencymay be enhanced through the use of any number of various filter mediathat include, without limitation, woven cloth fabrics, woven metalfabrics, porous metal substrates and synthetic or naturally occurringmembranes. The separation device and media can be permanent, replaceableor disposable. The catalyst solid alone may be separated, or separationmay be assisted by the use of porous cellulosic fiber or diatomaceoussilica type filter aids, which are used as a media precoat and/ordirectly with a catalyst slurry. The separation device can be operatedin an automated or manual mode for solid media washing, soliddischarging and/or solid and media back flushing. The catalyst can bewashed and discharged from the filter media using gas, liquid ormechanical means. The catalyst alone or catalyst with filter aid can bepartially or totally recycled for used in subsequent hydrogenationreactions.

The reaction mixture, if water is present, may be held for a time and ata temperature sufficient to hydrolyze dialkylated imidazolidinone toα-neotame and 3,3-dimethylbutyraldehyde. The reaction mixture isgenerally held for about 0.5-24 hours at a temperature of about 20-50°C. In a preferred embodiment of the present invention, the reactionmixture is held for about 2-4 hours.

Typically crystallization of neotame is accomplished by cooling themixture to about 0-25° C., preferably to about 5-10° C., over the courseof about 0.5-2 hours, preferably about 1-2 hours.

Seeding prior to or during crystallization can initiate a controlledcrystal growth rate according to the present invention. Hence, thereaction mixture may optionally be seeded in an amount from 0.0001%-10%,by weight of the N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine1-methyl ester in the solution, preferably from 0.1% to 1% and mostpreferably from 0.1% to 0.5%. Seeding is typically performed at 25-35°C. and preferably at 28-30° C.

The reaction mixture or the solution containing neotame may be unstirredor stirred according to any embodiment of the present invention.

Crystallized neotame may be separated from the solvent solution by avariety of solid-liquid separation techniques that utilize centrifugalforce, that include, without limitation, vertical and horizontalperforated basket centrifuge, solid bowl centrifuge, decantercentrifuge, peeler type centrifuge, pusher type centrifuge, Heinkel typecentrifuge, disc stack centrifuge and cyclone separation. Additionally,separation may be enhanced by any of pressure, vacuum, and gravityfiltration methods, that include, without limitation, the use of belt,drum, nutsche type, leaf, plate, Rosenmund type, sparkler type, and bagfilters and filter press. Operation of the neotame solid-liquidseparation device may be continuous, semi-continuous or in batch mode.The neotame solid may also be washed on the separation device usingvarious liquid solvents, including, without limitation, water, methanoland mixtures thereof. The neotame solid can also be partially andtotally dried on the separation device using any number of gases,including, without limitation, nitrogen and air, to evaporate residualliquid solvent. The neotame solid may be automatically or manuallyremoved from the separation device using liquids, gases or mechanicalmeans by either dissolving the solid or maintaining the solid form.

The neotame synthesized according to the present invention may bepurified by any known method including, but not limited to, thefollowing methods. U.S. Pat. No. 5,728,862 outlines a purificationmethod by which neotame is precipitated out of an aqueous/organicsolvent solution, wherein the aqueous/organic solvent solution has anamount of organic solvent of about 17% to about 30% by weight. U.S. Pat.No. 6,423,864 relates to methods of purifying neotame by crystallizationin a variety of organic solvent/aqueous organic solvent mixtures; eachof these methods involves the use of an organic solvent and watermixture and solvent distillation. Copending U.S. patent application Ser.No. 09/449,314, filed on Nov. 24, 1999, relates to methods of purifyingneotame using chromatography.

The neotame synthesized according to the present invention is themonohydrate, which may be dried to produce an anhydrous form.

The crystallized and isolated neotame solid may be further purified by avariety of drying methods. Such methods are known to those skilled inthe art and include, but are not limited to, the use of a rotary vacuumdryer, fluid bed dryer, rotary tunnel dryer, plate dryer, tray dryer,Nauta type dryer, spray dryer, flash dryer, micron dryer, pan dryer,high and low speed paddle dryer and microwave dryer.

The above-described process of the present invention achieves a numberof advantages as compared to conventional neotame synthetic routes. Inparticular, complicated processing steps to isolate3,3-dimethylbutyraldehyde prior to combining it with aspartame areeliminated. On a manufacturing scale, this results in processing timesavings, as well as a significant cost savings.

The examples which follow are intended as an illustration of certainpreferred embodiments of the invention, and no limitation of theinvention is implied.

EXAMPLE 1

Sodium bisulfite adduct of 3,3-dimethyl butylraldehyde (4.0 g), sodiumhydrogen carbonate (2.2 g) and water (20 mL) were charged to a 50 mLround bottom flask. The mixture was heated to boiling and distilled toyield an azeotropic mixture of 3,3-dimethylbutyraldehyde and water (b.p. 82-85° C.). To this azeotropic mixture was charged L-aspartame (4.0g, 13.5 mmol), methanol (50 mL) and 5% Pd/C (5%, 0.16 g). The mixturewas hydrogenated at 30 psi/room temperature for 12-16 hours. The mixturewas filtered through a Dicalite bed and the bed washed with methanol (5mL). The methanol was reduced to half (25 mL) on a rotary evaporatorunder reduced pressure at room temperature and then water (30 mL) wasadded to it. The remaining methanol was distilled to a level of 15-30%.The mixture was left stirring at room temperature for 2-12 hours. Theprecipitated solid was filtered, washed with water (50 mL) and dried ina vacuum oven at 40° C./house vac/16 hours to get 2.8 g (56%) of whitesolid (>97% pure by HPLC).

EXAMPLE 2

A slurry of L-aspartame (4.0 g, 13.5 mmol), dimethyl acetal of 3,3-dimethyl butylraldehyde (1.35 g, 13.5 mmol), methanol (50 mL) and 5%Pd/C (5%, 0.16 g) was hydrogenated at 30 psi/room temperature for 12-16hours. The mixture was filtered through a Dicalite bed and the bedwashed with methanol (5 mL). The methanol was reduced to half (25 mL) ona rotary evaporator under reduced pressure at room temperature and thenwater (30 mL) was added to it. The remaining methanol was distilled to alevel of 15-30%. The mixture was left stirring at room temperature for2-12 hours. The precipitated solid was filtered, washed with water (50mL) and dried in a vacuum oven at 40° C./house vac/16 hours to get 3.9 g(73%) of white solid (>97% pure by HPLC).

EXAMPLE 3

3,3-Dimethylbutanal (10.0 g, 0.1 mol) was cooled to 0° C. andconcentrated sulfuric acid (0.1 g) was added. Then, the reaction mixturewas cooled to −30° C. (the reaction mixture solidified at thistemperature) and kept for 2 hours at the same temperature. The mixturewas warmed to 0° C. and diethyl ether (30 mL) was added. The solutionwas washed with saturated aqueous sodium bicarbonate (2×30 mL) and withwater (2×30 mL). The extract was dried over magnesium sulfate andevaporated under reduced pressure (15 mm Hg, 40° C. water bath) to givecolorless solid (8.8 g). The NMR analysis showed desired2,4,6-trineopentyl-1,3,5-trioxane of 95% purity. The crude product wasdissolved in methanol (20 mL) and filtered. Then water (20 mL) wasslowly added to this solution and cooled to −20° C. for 1 hour. Thecolorless solid was separated, washed with water and dried in vacuum togive the pure product (7.5 g).

2,4,6-Trineopentyl-1,3,5-trioxane (3.3 g, about 10.7 mmol) was dissolvedin toluene (3 mL) and 0.5 mL of 20% aqueous hydrochloric acid was added.The mixture was refluxed under nitrogen atmosphere for 1 hour (68-69°C.). The NMR analysis showed the only signals corresponding to3,3-dimethylbutyraldehyde and benzene. The mixture was neutralized withsodium bicarbonate to pH=7 and the organic layer was transferred to thestirred suspension of aspartame (9.4 g, 31.9 mmol) and Pd/C (0.4 g) inmethanol (150 mL) under nitrogen. Nitrogen was removed by hydrogen andthe reaction mixture was vigorously stirred for 14 hours under lighthydrogen pressure (<1 psi). Then, the mixture was filtered throughCelite. The Celite layer was washed with methanol (25 mL) and evaporatedunder vacuum to half (about 80-90 mL), filtered and water (about 100 mL)was added to the residue. The mixture was gently evaporated under vacuumto remove methanol (without heating to keep low temperature of about0-5° C.), and then kept at room temperature for 24 hours. Theprecipitate was filtered off, washed with water (30 mL) and dried undervacuum for 14 hours to give neotame (6.88 g, 57%).

While the invention has been described in terms of preferred embodimentsand specific examples, those skilled in the art will recognize throughroutine experimentation that various changes and modifications can bemade without departing form the spirit and scope of the invention. Thus,the invention should be understood as not being limited by the foregoingdetailed description, but as being defined by the appended claims andtheir equivalents.

1. A process of synthesizingN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl estercomprising the steps of: hydrolyzing a bisulfite adduct of3,3-dimethylbutyraldehyde with a base in a solvent to produce3,3-dimethylbutyraldehyde in situ; and reacting the3,3-dimethylbutyraldehyde produced in situ withL-α-aspartyl-L-phenylalanine 1-methyl ester in the presence of acatalyst and hydrogen for a time and at a temperature sufficient toproduce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methylester.
 2. The process according to claim 1, wherein the bisulfite adductof 3,3-dimethylbutyraldehyde is used in an amount of about 0.90 to about1.1 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine1-methyl ester.
 3. The process according to claim 2, wherein thebisulfite adduct of 3,3-dimethylbutyraldehyde is used in an amount ofabout 0.98 to about 1.0 on an equivalent molar ratio basis withL-α-aspartyl-L-phenylalanine 1-methyl ester.
 4. The process according toclaim 1, wherein the base is selected from the group consisting ofsodium bicarbonate, potassium bicarbonate, sodium carbonate, potassiumcarbonate, zinc oxide, zinc carbonate, magnesium oxide, calcium oxide,aluminum oxide, magnesium carbonate, calcium carbonate, monobasicpotassium phosphate, dibasic potassium phosphate, tribasic potassiumphosphate, monobasic sodium phosphate, dibasic sodium phosphate,tribasic sodium phosphate, ammonium phosphate, calcium phosphate,magnesium phosphate, ammonia, a tertiary amine, a secondary amine, apyridine derivative, and combinations thereof.
 5. The process accordingto claim 1, wherein the base is present in an amount of about 1% toabout 10% by weight of the bisulfite adduct.
 6. The process according toclaim 1, wherein the catalyst is selected from the group consisting ofplatinum on activated carbon, palladium on activated carbon, platinumblack, palladium black, nickel on silica, nickel on alumina, Raneynickel, ruthenium black, ruthenium on carbon, palladium hydroxide oncarbon, palladium oxide, platinum oxide, rhodium black, rhodium oncarbon and rhodium on alumina.
 7. The process according to claim 1,wherein the weight ratio of catalyst on a dry basis toL-α-aspartyl-L-phenylalanine 1-methyl ester is from about 0.01:1 toabout 0.25:1.
 8. The process according to claim 1, wherein the solventis selected from the group consisting of ethanol, ethyl acetate,acetonitrile, dioxane, isopropanol, methanol, isobutyl methyl ketone,tetrahydrofuran, cyclohexane, toluene, dimethylformamide, water andmixtures thereof.
 9. The process according to claim 1, wherein thetemperature sufficient to produceN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester isfrom about 20° C. to about 60° C.
 10. The process according to claim 1,wherein the time sufficient to produceN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester isfrom about 1 hour to about 24 hours.
 11. The process according to claim1, wherein the pressure of the hydrogen is from about 5 psi to about 100psi.
 12. The process according to claim 1 further comprising the step ofneutralizing the solvent containing the 3,3-dimethylbutyraldehydeproduced in situ to have a pH ranging from about 3 to about
 7. 13. Aprocess of synthesizingN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl estercomprising the steps of: regenerating 3,3-dimethylbutyraldehyde from ahydrazone, a semicarbazone or an oxime of 3,3-dimethylbutyraldehyde in asolvent to produce 3,3-dimethylbutyraldehyde in situ; and reacting the3,3-dimethylbutyraldehyde produced in situ withL-α-aspartyl-L-phenylalanine 1-methyl ester in the presence of acatalyst and hydrogen for a time and at a temperature sufficient toproduce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methylester.
 14. The process according to claim 13, wherein the regeneratingstep comprises hydrolyzing the hydrazone, the semicarbazone or the oximeof 3,3-dimethylbutyraldehyde with an acid.
 15. The process according toclaim 14 further comprising the step of neutralizing the solventcontaining the 3,3-dimethylbutyraldehyde produced in situ to have a pHranging from about 3 to about
 7. 16. The process according to claim 14,wherein the acid is selected from the group consisting of acetic acid,citric acid, nitrous acid and combinations thereof.
 17. The processaccording to claim 14, wherein the acid is present in an amount of about1% to about 10% by weight of the hydrazone, the semicarbazone or theoxime of 3,3-dimethylbutyraldehyde.
 18. The process according to claim13, wherein the regenerating step comprises oxidatively cleaving thehydrazone, the semicarbazone or the oxime of 3,3-dimethylbutyraldehydewith an oxidative agent.
 19. The process according to claim 18, whereinthe oxidative agent is selected from the group consisting ofm-chloroperbenzoic acid, ozone, sodium periodate, diacetoxyiodobenzene,iodosobenzene, and combinations thereof.
 20. The process according toclaim 18, wherein the oxidative agent is present in an amount of about0.5 to about 3.0 on an equivalent molar ratio basis with the hydrazone,the semicarbazone or the oxime of 3,3-dimethylbutyraldehyde.
 21. Theprocess according to claim 13, wherein the hydrazone, the semicarbazoneor the oxime of 3,3-dimethylbutyraldehyde is used in an amount of about0.90 to about 1.1 on an equivalent molar ratio basis withL-α-aspartyl-L-phenylalanine 1-methyl ester.
 22. The process accordingto claim 21, wherein the hydrazone, the semicarbazone or the oxime of3,3-dimethylbutyraldehyde is used in an amount of about 0.98 to about1.0 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine1-methyl ester.
 23. The process according to claim 13, wherein thecatalyst is selected from the group consisting of platinum on activatedcarbon, palladium on activated carbon, platinum black, palladium black,nickel on silica, nickel on alumina, Raney nickel, ruthenium black,ruthenium on carbon, palladium hydroxide on carbon, palladium oxide,platinum oxide, rhodium black, rhodium on carbon and rhodium on alumina.24. The process according to claim 13, wherein the weight ratio ofcatalyst on a dry basis to L-α-aspartyl-L-phenylalanine 1-methyl esteris from about 0.01:1 to about 0.25:1.
 25. The process according to claim13, wherein the solvent is selected from the group consisting ofethanol, ethyl acetate, acetonitrile, dioxane, isopropanol, methanol,isobutyl methyl ketone, tetrahydrofuran, cyclohexane, toluene,dimethylformamide, water and mixtures thereof.
 26. The process accordingto claim 13, wherein the temperature sufficient to produceN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester isfrom about 20° C. to about 60° C.
 27. The process according to claim 13,wherein the time sufficient to produceN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester isfrom about 1 hour to about 24 hours.
 28. The process according to claim13, wherein the pressure of the hydrogen is from about 5 psi to about100 psi.
 29. A process of synthesizingN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl estercomprising the steps of: hydrolyzing a trimer of3,3-dimethylbutyraldehyde with an acid in a solvent to produce3,3-dimethylbutyraldehyde in situ; and reacting the3,3-dimethylbutyraldehyde produced in situ withL-α-aspartyl-L-phenylalanine 1-methyl ester in the presence of acatalyst and hydrogen for a time and at a temperature sufficient toproduce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methylester.
 30. The process according to claim 29, wherein the trimer of3,3-dimethylbutyraldehyde is used in an amount of about 0.3 to about 1.1on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine1-methyl ester.
 31. The process according to claim 30, wherein thetrimer of 3,3-dimethylbutyraldehyde is used in an amount of about 0.33to about 0.35 on an equivalent molar ratio basis withL-α-aspartyl-L-phenylalanine 1-methyl ester.
 32. The process accordingto claim 29, wherein the acid is selected from the group consisting ofhydrochloric acid, acetic acid, sulfuric acid and combinations thereof.33. The process according to claim 29, wherein the acid is present in anamount of about 1% to about 20% by weight of the trimer.
 34. The processaccording to claim 29, wherein the catalyst is selected from the groupconsisting of platinum on activated carbon, palladium on activatedcarbon, platinum black, palladium black, nickel on silica, nickel onalumina, Raney nickel, ruthenium black, ruthenium on carbon, palladiumhydroxide on carbon, palladium oxide, platinum oxide, rhodium black,rhodium on carbon and rhodium on alumina.
 35. The process according toclaim 29, wherein the weight ratio of catalyst on a dry basis toL-α-aspartyl-L-phenylalanine 1-methyl ester is from about 0.01:1 toabout 0.25:1.
 36. The process according to claim 29, wherein the solventis selected from the group consisting of ethanol, ethyl acetate,acetonitrile, dioxane, isopropanol, methanol, isobutyl methyl ketone,tetrahydrofuran, cyclohexane, toluene, dimethylformamide, water andmixtures thereof.
 37. The process according to claim 29, wherein thetemperature sufficient to produceN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester isfrom about 20° C. to about 60° C.
 38. The process according to claim 29,wherein the time sufficient to produceN—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester isfrom about 1 hour to about 24 hours.
 39. The process according to claim29, wherein the pressure of the hydrogen is from about 5 psi to about100 psi.
 40. The process according to claim 29 further comprising thestep of neutralizing the solvent containing the3,3-dimethylbutyraldehyde produced in situ to have a pH ranging fromabout 3 to about 7.